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J Neurol (2009) 256:271–273DOI 10.1007/s00415-009-0921-3
LETTER TO THE EDITORS
J O N 2 9 2 1
the presence of the
tRNA
Lys
A8344G mutation.This 17-year-old patient had normal growth until eight years of age when sensorineural deafness, gait instability, easy fatigability, dif-ficulty with fine movements of the hands, as in writing, failure to grow and hypothyroidism gradually de-veloped. At the age of 12 years, val-proic acid was administered due to seizures. She showed increased serum and CSF lactate and in-creased urinary excretion of amino acids. A muscle biopsy was declined. At the age of 14 years lamotrigine was given, due to increased seizure frequency and, later, levetiracetam was substituted for valproic acid. At 16 years of age lack of menarche, polycystic ovaries and myoclonic jerks were noted. In September 2006, she developed diplopia that lasted for approximately 20 days. In January 2007, the patient was admitted to our service because of dysarthria, dysphagia, respiratory difficulties and worsening of gait ataxia. On examination, there was marked slowness of the saccadic eye move-ments with the smooth pursuit be-ing less affected. Convergence was impaired. Speech was dysarthric and dysrhythmic, the gag reflex diminished bilaterally and the palate high arched. Deep tendon reflexes were markedly increased, with sustained ankle clonus and extensor plantar responses. Pos-tural and intention tremor and dysmetria and dysdiachokinesia were present on all four extremi-ties. Pes cavus was observed bilat-erally. Due to respiratory difficul-ties associated with repeated respiratory infections, a tracheos-tomy was performed and the pa-tient received mechanical ventila-tion intermittently. Bulbar function gradually improved.Brain MRIs in March 2006 and in September 2006 showed a focal, non-enhancing, T2 hyperintense
Ioannis ZaganasHelen LatsoudisEufrosini PapadakiPelagia VorgiaMartha SpiliotiAndreas Plaitakis
A8344G tRNA
Lys
mutation associated with recurrent brain stem stroke-like episodes
Received: 25 November 2007Received in revised form: 21 January 2008Accepted: 15 February 2008Published online: 27 February 2009
Sirs: Among the commonest mito-chondriopathies are MELAS (mito-chondrial encephalomyopathy and lactic acidosis with stroke-like episodes) and MERRF (myoclonic epilepsy with red ragged fibers) syndromes [1]. The majority of MELAS patients carry the
tRNA
Leu(UUR)
A3243G mutation in their mitochondrial DNA (mtDNA), whereas those with MERRF the
tRNA
Lys
A8344G mutation.Here we describe a patient with MERRF syndrome who experi-enced step-wise neurological dete-rioration associated with recurrent migratory brainstem stroke-like episodes. Genetic testing revealed lesion in the right midbrain teg-mentum (Fig. 1). In January 2007, another MRI revealed a new lesion in the right lateral medulla while the lesion at the right midbrain tegmentum had almost completely resolved (Fig. 1). Magnetic reso-nance spectroscopy failed to reveal increased levels of brain lactate, although serum lactate levels were increased (22 mg/dl). Nerve con-duction studies revealed mild poly-neuropathy, but no myopathy. Elec-troencephalography revealed generalized discharges of slow-wave and spike-wave complexes.Sequencing of mtDNA obtained from peripheral leucocytes re-vealed the presence of the A8344G mutation in almost homoplasmic state in the patient (Fig. 2). The mother of the patient carried the same mutation in heteroplasmic state, whereas the father was homo-plasmic for the normal sequence. Examination of the mother re-vealed a small cervical lipoma. The father and the brother of the pa-tient were normal. A maternal aunt of the patient had a history of dys-thyroid condition. No other family member is known to be affected by seizure disorder or myopathy.The A8344G mutation is found in the majority of patients present-ing with the typical MERRF syn-drome. However, this mutation has also been associated with a variety of other presentations, including Leigh’s syndrome, progressive external opthalmoplegia, multiple lipomas, cardiomyopathy and parkinsonism [2–5]. As in other mtDNA mutations, the pathogenic-ity of the A8344G mutation de-pends on a variety of factors, such as the ratio of mutant to wild-type mtDNAs within tissues, within cells and even within individual mito-chondria, the energy requirements of each tissue, environmental fac-tors and the nuclear genetic back-ground [2, 6].The predilection for migratory
I. Zaganas, MD, PhD · H. Latsoudis, PhD · M. Spilioti, MD, PhD · Prof. A. Plaitakis, MD, PhD (

)Neurology DepartmentUniversity Hospital of Crete71110 Herakion, Crete, GreeceTel.: +30-2810/394648Fax: +30-2810/392052E-Mail: plaitak@med.uoc.grE. Papadaki, MD, PhDRadiology DepartmentUniversity Hospital of Crete71110 Herakion, Crete, GreeceP. Vorgia, MD, PhDMother and Child Health DepartmentUniversity Hospital of Crete71110 Herakion, Crete, Greece
272
brain stem lesions observed in our patient is unusual in mitochondrial encephalopathies. Stroke-like epi-sodes are localized predominantly in the cerebral hemispheres in MELAS patients and in the rare MERRF patients harboring the A8344G mutation who present such episodes (7, 8, 9, 10). When the clinical features of MERRF are associated with stroke-like episodes, as is the case in our patient, the syndrome is commonly described as MERRF/MELAS over-lap syndrome. However, the mito-chondrial mutations associated with previously described cases of MERRF/MELAS overlap syndrome have been the tRNA
Leu(UUR)
A3243G [11], the tRNA
Lys
(T8356C) [12], the tRNA
Ser
(T7512C) [13], the tRNA
His
(G12147A) [14] and the G13042A mutation of the subunit 5 of com-plex I (ND5) [15].A mtDNA mutation can be asso-ciated with markedly different phe-notypes and different clinical syn-dromes can be associated with the same mitochondrial mutation [1, 2]. This report extends further the phenotypic variability of the mito-chondrial disorders and highlights the importance of retaining a high level of suspicion for these disor-ders, even in atypical presentations such as brainstem stroke-like epi-sodes.
■
Acknowledgments
The authors wish to acknowledge the valuable help of Dr. G. Amoiridis, Dr. G. Gavriilidis and the medi-cal and nursing staff of the Neurology De-partment of the University Hospital of Crete. This work was supported by the As-sociation for Research and Treatment of Neurological Disorders of Crete “EY ZHN”.
■
Disclosure
The authors report no con-flicts of interest.
References
1. DiMauro S, Schon E (2003) Mitochon-drial respiratory-chain diseases. N Engl J Med 348:2656–2668 2. Schapira AH (2006) Mitochondrial disease. Lancet 368:70–82 3. Horvath R, Kley RA, Lochmüller H, Vorgerd M (2007) Parkinson syn-drome, neuropathy, and myopathy caused by the mutation A8344G MERRF) in tRNALys. Neurology 68:56–58 4. Larsson NG, Tulinius MH, Holme E, et al. (1992) Segregation and manifes-tations of the mtDNA tRNA(Lys) A-->G(8344) mutation of myoclonus epilepsy and ragged-red fibers (MERRF) syndrome. Am J Hum Genet. 51:1201–1212 5. Holme E, Larsson NG, Oldfors A, et al. (1993) Multiple symmetric lipomas with high levels of mtDNA with the tRNA(Lys) A-->G(8344) mutation as the only manifestation of disease in a carrier of myoclonus epilepsy and ragged-red fibers (MERRF) syndrome. Am J Hum Genet 52:551–556
Fig. 1
MRI Imaging studies. Upper panel (
A, B, C, D
): MRI studies obtained in March 2006 showing a stroke-like lesion in the right side of the midbrain tegmentum causing a slight mass effect. Lower panel (
E, F, G, H
): MRI study obtained in January 2007 showing remarkable resolution of the midbrain lesion and the appearance of a new lesion with similar imaging features in the right lateral medulla
273
6. Moslemi AR, Tulinius M, Holme E, Oldfors A (1998) Threshold expression of the tRNA(Lys) A8344G mutation in single muscle fibres. Neuromuscul Disord 8:345–349 7. Noer A, Sudoyo H, Lertrit P, et al. (1991) A tRNA(Lys) mutation in the mtDNA is the causal genetic lesion underlying myoclonic epilepsy and ragged-red fiber (MERRF) syndrome. Am J Hum Genet 49:715–722 8. Hammans S, Sweeney M, Brockington M, et al. (1993) The mitochondrial DNA transfer RNA(Lys)A-->G(8344) mutation and the syndrome of myo-clonic epilepsy with ragged red fibres (MERRF). Relationship of clinical phe-notype to proportion of mutant mito-chondrial DNA. Brain 116:617–632 9. Tanji K, Gamez J, Cervera C, et al. (2003) The A8344G mutation in mito-chondrial DNA associated with stroke-like episodes and gastrointestinal dys-function. Acta Neuropathol (Berl) 105:69–7510. Chinnery P, Howell N, Lightowlers R, Turnbull D (1997) Molecular pathol-ogy of MELAS and MERRF. The rela-tionship between mutation load and clinical phenotypes. Brain 120:1713–172111. Campos Y, Martin M, Lorenzo G, et al. (1996) Sporadic MERRF/MELAS over-lap syndrome associated with the 3243 tRNA(Leu(UUR)) mutation of mito-chondrial DNA. Muscle Nerve 19:187–19012. Zeviani M, Muntoni F, Savarese N, et al. (1993) A MERRF/MELAS overlap syndrome associated with a new point mutation in the mitochondrial DNA tRNA(Lys) gene. Eur J Hum Genet 1:80–8713. Nakamura M, Nakano S, Goto Y, et al. (1995) A Novel Point Mutation in the Mitochondrial tRNASer(UCN) Gene Detected in a Family with MERRF/MELAS Overlap Syndrome. Bioch Bioph Res Com 214:86–9314. Melone M, Tessa A, Petrini S, et al. (2004) Revelation of a new mitochon-drial DNA mutation (G12147A) in a MELAS/MERFF phenotype. Arch Neurol 61:269–27215. Naini A, Lu J, Kaufmann P, et al. (2005) Novel mitochondrial DNA ND5 muta-tion in a patient with clinical features of MELAS and MERRF. Arch Neurol 62:473–476
Fig. 2
Family tree and genetic testing results for the patient, her mother and her father. Results showed the presence of the A8344G mutation in homoplasmic state in the patient and in heteroplasmic state in her mother. Attached are the chromatograms for each individual

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